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Diminished reward responsiveness is associated with lower reward network GluCEST: an ultra-high field glutamate imaging study

Molecular Psychiatry volume 26, pages 2137–2147 (2021)Cite this article

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Abstract

Low reward responsiveness (RR) is associated with poor psychological well-being, psychiatric disorder risk, and psychotropic treatment resistance. Functional MRI studies have reported decreased activity within the brain’s reward network in individuals with RR deficits, however the neurochemistry underlying network hypofunction in those with low RR remains unclear. This study employed ultra-high field glutamate chemical exchange saturation transfer (GluCEST) imaging to investigate the hypothesis that glutamatergic deficits within the reward network contribute to low RR. GluCEST images were acquired at 7.0 T from 45 participants (ages 15–29, 30 females) including 15 healthy individuals, 11 with depression, and 19 with psychosis spectrum symptoms. The GluCEST contrast, a measure sensitive to local glutamate concentration, was quantified in a meta-analytically defined reward network comprised of cortical, subcortical, and brainstem regions. Associations between brain GluCEST contrast and Behavioral Activation System Scale RR scores were assessed using multiple linear regressions. Analyses revealed that reward network GluCEST contrast was positively and selectively associated with RR, but not other clinical features. Follow-up investigations identified that this association was driven by the subcortical reward network and network areas that encode the salience of valenced stimuli. We observed no association between RR and the GluCEST contrast within non-reward cortex. This study thus provides new evidence that reward network glutamate levels contribute to individual differences in RR. Decreased reward network excitatory neurotransmission or metabolism may be mechanisms driving reward network hypofunction and RR deficits. These findings provide a framework for understanding the efficacy of glutamate-modulating psychotropics such as ketamine for treating anhedonia.

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Fig. 1: Overview of structural and GluCEST processing.
Fig. 2: Association between dimensional reward responsiveness and reward network GluCEST.
Fig. 3: Association between dimensional reward responsiveness and subcortical reward network GluCEST.
Fig. 4: Effect size determined by valence encoding.

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Code availability

All analytic code is available at https://github.com/PennLINC/sydnor_glucest_rewardresponsiveness_2020.

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Acknowledgements

We would like to thank the recruitment team at the Penn-CHOP Lifespan Brain Institute, led by Thomas Hohing, Karthik Prabhakaran, and Jacqueline Meeks, for assistance with 7.0 T MRI data collection.

Funding

This work was supported by National Institute of Mental Health R01s MH119185 (DRR) and MH120174 (DRR), a National Institute of Aging R56 AG066656 (DRR), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (DRR), a University of Pennsylvania Research Foundation Grant (DRR), and the University of Pennsylvania Institute for Translational Medicine and Therapeutics (TDS, JFY). Additional support was provided by R01 MH119219 (REG, RCG), R01 MH113565 (DHW), R01 MH107703 (TDS), R01 MH112847 (TDS, RTS), T32 MH014654-43 (BL), P41 NIBIB EB015893 (RR), and the Lifespan Brain Institute—a collaboration between the University of Pennsylvania School of Medicine and Children’s Hospital of Philadelphia. The funding sources were not directly involved in study design, data collection, data analysis, data interpretation, or manuscript writing.

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Authors and Affiliations

  1. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Valerie J. Sydnor, Bart Larsen, Christian Kohler, Andrew J. D. Crow, Sage L. Rush, Monica E. Calkins, Ruben C. Gur, Raquel E. Gur, Kosha Ruparel, Jami F. Young, Daniel H. Wolf, Theodore D. Satterthwaite & David R. Roalf

  2. Lifespan Brain Institute, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA

    Christian Kohler, Monica E. Calkins, Ruben C. Gur, Raquel E. Gur, Kosha Ruparel, Jami F. Young, Daniel H. Wolf, Theodore D. Satterthwaite & David R. Roalf

  3. Department of Psychology, University of Pennsylvania, Philadelphia, PA, USA

    Joseph W. Kable

  4. MindCORE, University of Pennsylvania, Philadelphia, PA, USA

    Joseph W. Kable

  5. Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA

    Sanjeev Chawla, Mark A. Elliott, Ravi Prakash Reddy Nanga & Ravinder Reddy

  6. Penn Statistics in Imaging and Visualization Endeavor, Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Russell T. Shinohara

  7. Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Russell T. Shinohara, Daniel H. Wolf & Theodore D. Satterthwaite

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  1. Valerie J. Sydnor
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Sydnor, V.J., Larsen, B., Kohler, C. et al. Diminished reward responsiveness is associated with lower reward network GluCEST: an ultra-high field glutamate imaging study. Mol Psychiatry 26, 2137–2147 (2021). https://doi.org/10.1038/s41380-020-00986-y

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